Synchronization of electrical field potentials in neocortex of rat after isolation of a cortex island in the contralateral brain hemisphere

A correlation between the number of boutons and synchronization of electrical activity in two sites of the intact right somatosensory cortex of rats was anakyzed at different stages of axonal sprouting elicited by isolation of a cortex slab in the left cortex. Time delay between the development of epileptiform field potentials in two sites of intact cortex located at a distance of 4 mm from each other was determined as a parameter of synchronization. The analysis was carried out in 30 and 90 days after the complete isolation of the neural island in a symmetrical site of the contralateral cortex. Epileptiform activity was induced by penicillin. A significant increase in the number of boutons in the II and V layers of the intact cortex observed 90 days after the isolation of neural island in a symmetrical site of the cortex corresponded to a significant decrease in the delay of electrical activity development. Similar effects were observed in the V layer of the island 30 days after the isolation. The results suggest that the cortex lesion activates formation of new synaptic boutons in a contralateral site and increases a degree of synchronization of electrical activity, which may affect the epileptogenesis. The data suggest that pyramids of the III and, most probably, V layers form a neuronal network in the rat neocortex thus providing synchronization of epileptiform field potentials.     

Structural basis of the intracortical synchronization of epileptic potentials in the sensomotor region of the rat neocortex

In control rats, penicillin-induced epileptiform discharges were completely synchronous in the neocortex sites at a distance of up to 4 mm from each other. Number of the cells decreased by 45.5% during 90 days in isolated cortical slabs and the synchronisation disappeared. The data obtained show that the loss of large pyramidal neurones of the layer V entailed a loss of the spatial synchronisation. The main axonal collaterals of large pyramidal neurones of the layer V could be followed horizontally for a distance of up to 2 mm in the somatosensory cortex. The neuronal network formed by the large pyramidal neurones of the layer V seems to provide a spatial synchronisation in the neocortex.     

Glutamate producing aspartate aminotransferase in glutamatergic perforant path terminals of the rat hippocampus

Summary The enzyme aspartate aminotransferase was demonstrated cytochemically in the rat hippocampus 4, 7, and 14 days after unilateral entorhinal cortex lesion. At the light microscopic level the enzyme showed a significant activity decrease in the ipsilateral entorhinal terminal field which was similar at all postlesion times investigated. Non-denervated areas, i.e. the inner one-third of the dentate gyrus molecular layer and the radiatum layer of CA2/3, showed an increase of aminotransferase activities. At the electron microscopic level in the entorhinal terminal field of the control (unoperated) side aspartate aminotransferase was localized preferentially in a great number of boutons, containing the cytoplasmic and mitochondrial isoenzymes. Following entorhinal lesion a significant loss of these positively reacting boutons was seen. Most of the degenerating boutons contained reaction product but a small number was negative for aspartate aminotransferase. From 4 to 14 postlesion days the positively reacting boutons of the non-denervated supragranular zone expanded outward into the denervated area according to the known terminal proliferation of the commissural and associational systems. The remaining denervated entorhinal terminal field was reinnervated predominantly by negatively reacting boutons (probably terminal proliferations of septal afferents) and by a small number of positively reacting boutons (probably terminal proliferations of the crossed temporodentate pathway). The presence of cytoplasmic aspartate aminotransferase in the terminals of a well-known glutamatergic system is discussed in relation to the possible importance of this enzyme for the production of releasable glutamate.     

Glutamate producing aspartate aminotransferase in glutamatergic perforant path terminals of the rat hippocampus. Cytochemical and lesion studies

The enzyme aspartate aminotransferase was demonstrated cytochemically in the rat hippocampus 4, 7, and 14 days after unilateral entorhinal cortex lesion. At the light microscopic level the enzyme showed a significant activity decrease in the ipsilateral entorhinal terminal field which was similar at all postlesion times investigated. Non-denervated areas, i.e. the inner one-third of the dentate gyrus molecular layer and the radiatum layer of CA2/3, showed an increase of aminotransferase activities. At the electron microscopic level in the entorhinal terminal field of the control (unoperated) side aspartate aminotransferase was localized preferentially in a great number of boutons, containing the cytoplasmic and mitochondrial isoenzymes. Following entorhinal lesion a significant loss of these positively reacting boutons was seen. Most of the degenerating boutons contained reaction product but a small number was negative for aspartate aminotransferase. From 4 to 14 postlesion days the positively reacting boutons of the non-denervated supragranular zone expanded outward into the denervated area according to the known terminal proliferation of the commissural and associational systems. The remaining denervated entorhinal terminal field was reinnervated predominantly by negatively reacting boutons (probably terminal proliferations of septal afferents) and by a small number of positively reacting boutons (probably terminal proliferations of the crossed temporo-dentate pathway). The presence of cytoplasmic aspartate aminotransferase in the terminals of a well-known glutamatergic system is discussed in relation to the possible importance of this enzyme for the production of releasable glutamate.     

Epileptiform curents in rat cortical neurons increase over time of the in vitro culture period

Here we show that in primary culture of rat cortical neurons the number of episodes of epileptiform curents (EC) provoked by extracellular magnesium removal increases over time. We demonstrate that NMDA receptor agonists in low concentrations induce an elevation of frequency of miniature postsynaptic currents followed by their synchronization resulting in EC. Ifenprodil did not block EC but strongly inhibited NMDA-evoked whole-cell currents, which say for a key role of the ifenprodil-resistant synaptic GluN2A-containing NMDA receptors in the generation of EC. We suppose that in cultured neurons the onset of EC and a gradual increase of the EC amplitude over the time of culture period is directed by an increase of synaptic connections density and displacement of the GluN2B subunit by GluN2A in synapses.     

Development and specificity of inhibitory terminal arborizations in the central nervous system

This study examined the morphological development of single inhibitory arborizations in the gerbil central auditory brain stem. Using a brain slice preparation, neurons of the medial nucleus of the trapezoid body (MNTB) were filled with horseradish peroxidase (HRP), and their complete arborizations were analyzed along the tonotopic axis of the lateral superior olive (LSO). The projections in neonatal animals displayed well-defined arbors that were ordered appropriately within the LSO. It was evident from the axonal pathways that the MNTB afferents could correct for projection errors after reaching the postsynaptic population. As development progressed, a number of arbors established diffuse or inappropriate projections within the LSO. These immature arborizations were no longer apparent by 18–25 days postnatal. The anatomical specificity of arbors at 12–13 and 18–25 days was quantified by measuring the distance that terminal boutons spread across the frequency axis. There was a significant reduction of this distance in older animals. In addition, there was a significant reduction in the mean number of boutons per arbor between 12–13 days and 18–25 days. The maximum nucleus cross-sectional area continued to increase through 15–16 days, indicating that the refined arbors occupied an even smaller fraction of the postsynaptic structure. Taken together, these observations suggest that central inhibitory arbors form exuberant contacts that must be eliminated during development.     

Development and specificity of inhibitory terminal arborizations in the central nervous system.

This study examined the morphological development of single inhibitory arborizations in the gerbil central auditory brain stem. Using a brain slice preparation, neurons of the medial nucleus of the trapezoid body (MNTB) were filled with horseradish peroxidase (HRP), and their complete arborizations were analyzed along the tonotopic axis of the lateral superior olive (LSO). The projections in neonatal animals displayed well-defined arbors that were ordered appropriately within the LSO. It was evident from the axonal pathways that the MNTB afferents could correct for projection errors after reaching the postsynaptic population. As development progressed, a number of arbors established diffuse or inappropriate projections within the LSO. These immature arborizations were no longer apparent by 18-25 days postnatal. The anatomical specificity of arbors at 12-13 and 18-25 days was quantified by measuring the distance that terminal boutons spread across the frequency axis. There was a significant reduction of this distance in older animals. In addition, there was a significant reduction in the mean number of boutons per arbor between 12-13 days and 18-25 days. The maximum nucleus cross-sectional area continued to increase through 15-16 days, indicating that the refined arbors occupied an even smaller fraction of the postsynaptic structure. Taken together, these observations suggest that central inhibitory arbors form exuberant contacts that must be eliminated during development.     

Constitutive expression of p21H-ras(Val12) in pyramidal neurons results in reorganization of mouse neocortical afferents

The effect of constitutive expression of p21H-ras(Val12) in pyramidal neurons upon the establishment of afferent input has been investigated in the primary somatosensory cortex of transgenic mice. In these animals, relevant transgene expression is confined to cortical pyramidal neurons and starts postnatally at a period when neuronal morphogenesis has been largely completed. We have shown recently that overexpression of p21H-ras(Val12) in these cells results in considerable enlargement of their size and consequently in expansion of the cortex. In the present study we demonstrate that the density of terminals representing intra- or interhemispheric afferents within cortical layers II/III, however, is only slightly decreased. The density of thalamocortical boutons within layer IV is even higher and the number of afferent contacts to transgenic pyramidal neurons is significantly increased compared to the wild-type. The number of catecholaminergic and cholinergic terminals is augmented proportionally to cortical size or even overproportionally, respectively. Along intercortical and striatal fibers arising from p21H-ras(Val12)-expressing pyramidal neurons, frequency of varicosities is significantly increased, but remains unchanged on cortical cholinergic and catecholaminergic axons originating from "nontransgenic" neurons. Additionally, a higher number of multiple synaptic bodies are found in transgenic mice, suggesting subtle effects on synaptic plasticity. It is concluded that the enlargement of pyramidal neurons due to transgenic expression of p21H-ras(Val12) is paralleled by significant changes in the quantity and pattern of afferent connections. Moreover, expression of p21H-ras(Val12) in pyramidal cells induces an enhanced establishment of efferent boutons.     

Inhibition of axoplasmic transport in the developing visual system of the rat: IV. Quantitative Golgi, electron microscopic, and histochemical analyses of the maturation of the visual cortex

Intraocularly injected colchicine suppresses axonal transport within the developing rat's optic nerve throughout the critical period of visual system development. This results in a stunting of retinofugal terminals and relay neurons in the lateral geniculate nucleus. The present study focuses upon the effects of this unique form of developmental deprivation on the maturation of the visual cortex. Colchicine, in concentrations of from 10(-5) to 10(-2) M, was injected into the eyes of albino rats at birth or at 5, 10, or 15 days of age. Litters were killed at 5 to 50 days after this single injection, and the brains were processed for Nissl, rapid Golgi, histochemical, or electron microscopic analysis. The following results were obtained: Planimetry of coronal sections of the striate cortex revealed a reduction in the thickness of the cortex and in the ratio of neuropil area to neuronal soma area contralateral to the injected eye which was confined principally to layer IV, lower layer III, and upper layer V. This effect was inversely related to postnatal age at injection and directly proportional to colchicine concentration. A rapid Golgi analysis of 51 pairs of layer V pyramidal neurons in control and experimental cortex demonstrated a reduction in the number and size of spines along the portion of the apical dendrite passing through lower layer III and IV following colchicine administration at birth or 5 or 10 days of age but no significant change in the branching pattern of the entire dendritic arbor. Electron microscopy revealed a reduction in the number of small, asymmetric synaptic complexes with the result that the average size of remaining profiles was increased in layers III and IV. Histochemical analysis of cortical succinic dehydrogenase and cytochrome oxidase revealed a distinct band of intense enzyme activity in lower layers III and IV in normal cortex at 20-30 days of age. This band was significantly reduced in intensity after neonatal injection of colchicine as shown by densitometric measurements and comparison of experimental and control cortex. It is concluded that the geniculocortical projection, while not affected directly by colchicine administration, is altered by the secondary effects of axonal transport suppression, leading to an alteration in the establishment of cortical synaptic patterns and arborizations of their postsynaptic neurons whose dendrites are located in those layers recipient to this projection.     

Epileptiform activity in a neocortical network: a mathematical model

 A simple mathematical model describing the generation and propagation of epileptiform activity in a cerebral cortical network is presented. The model consists of a system of nonlinear delay differential equations. Physiological properties are taken into account as nonlinear transmission of signals at the synapse, temporal and spatial summation of incoming signals at the soma, active membrane characteristics, and dendritic and axonal propagation times. The influence of the connectivity and the temporal parameters on the oscillatory properties of the model is studied. The computer simulations are in agreement with experimental observations in cortical networks: whereas a weak excitatory or strong inhibitory synaptic connection strength produces a stationary status with short-lasting responses to external stimuli, increases in excitation or decreases in inhibition induce spontaneous and stimulus-evoked rhythmic discharges. Synaptic burst-like activity is observed only for an intermediate range of excitatory and inhibitory connection strengths and external inputs. The form and duration of the bursts can also be controlled by the temporal parameters. The results demonstrate that relatively simple mathematical equations are sufficient to model some of the network properties underlying the generation and propagation of epileptiform activity. Received: 2 October 2000 / Accepted in revised form: 4 March 2001     

The dendritic spines of the pyramidal neurons in layer V of the rat sensorimotor cortex following a 14-day space flight]

There was made a quantitative study of the influence of 14 days space flight ("Kosmos-2044") on dendritic spine (DS) density of the layer V pyramidal neurons of rat sensomotor cortex. There was found an increase of the number of apical DS lying in the layers III-IV in the flight group only. Number of DS on oblique dendrites was increased in the III-IV cortical layers both in the flight and tail-suspended rats. There was also an increase in the number of DS on basal dendrites in all experimental groups. Obtained data are compared with similar 7 days flight results ("Kosmos-1667") and other data of nervous tissue plasticity in weightlessness.     

Thalamic circuitry and thalamocortical synchrony

The corticothalamic system has an important role in synchronizing the activities of thalamic and cortical neurons. Numerically, its synapses dominate the inputs to relay cells and to the gamma-amino butyric acid (GABA)ergic cells of the reticular nucleus (RTN). The capacity of relay neurons to operate in different voltage-dependent functional modes determines that the inputs from the cortex have the capacity directly to excite the relay cells, or indirectly to inhibit them via the RTN, serving to synchronize high- or low-frequency oscillatory activity respectively in the thalamocorticothalamic network. Differences in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subunit composition of receptors at synapses formed by branches of the same corticothalamic axon in the RTN and dorsal thalamus are an important element in the capacity of the cortex to synchronize low-frequency oscillations in the network. Interactions of focused corticothalamic axons arising from layer VI cortical cells and diffuse corticothalamic axons arising from layer V cortical cells, with the specifically projecting core relay cells and diffusely projecting matrix cells of the dorsal thalamus, form a substrate for synchronization of widespread populations of cortical and thalamic cells during high-frequency oscillations that underlie discrete conscious events.     

Constitutive expression of p21H‐rasVal12 in pyramidal neurons results in reorganization of mouse neocortical afferents

The effect of constitutive expression of p21H‐ras^Val12 in pyramidal neurons upon the establishment of afferent input has been investigated in the primary somatosensory cortex of transgenic mice. In these animals, relevant transgene expression is confined to cortical pyramidal neurons and starts postnatally at a period when neuronal morphogenesis has been largely completed. We have shown recently that overexpression of p21H‐ras^Val12 in these cells results in considerable enlargement of their size and consequently in expansion of the cortex. In the present study we demonstrate that the density of terminals representing intra‐ or interhemispheric afferents within cortical layers II/III, however, is only slightly decreased. The density of thalamocortical boutons within layer IV is even higher and the number of afferent contacts to transgenic pyramidal neurons is significantly increased compared to the wild‐type. The number of catecholaminergic and cholinergic terminals is augmented proportionally to cortical size or even overproportionally, respectively. Along intercortical and striatal fibers arising from p21H‐ras^Val12‐expressing pyramidal neurons, frequency of varicosities is significantly increased, but remains unchanged on cortical cholinergic and catecholaminergic axons originating from “nontransgenic” neurons. Additionally, a higher number of multiple synaptic bodies are found in transgenic mice, suggesting subtle effects on synaptic plasticity. It is concluded that the enlargement of pyramidal neurons due to transgenic expression of p21H‐ras^Val12 is paralleled by significant changes in the quantity and pattern of afferent connections. Moreover, expression of p21H‐ras^Val12 in pyramidal cells induces an enhanced establishment of efferent boutons. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 263–274, 2004     

The Role of Thalamic Population Synchrony in the Emergence of Cortical Feature Selectivity

In a wide range of studies, the emergence of orientation selectivity in primary visual cortex has been attributed to a complex interaction between feed-forward thalamic input and inhibitory mechanisms at the level of cortex. Although it is well known that layer 4 cortical neurons are highly sensitive to the timing of thalamic inputs, the role of the stimulus-driven timing of thalamic inputs in cortical orientation selectivity is not well understood. Here we show that the synchronization of thalamic firing contributes directly to the orientation tuned responses of primary visual cortex in a way that optimizes the stimulus information per cortical spike. From the recorded responses of geniculate X-cells in the anesthetized cat, we synthesized thalamic sub-populations that would likely serve as the synaptic input to a common layer 4 cortical neuron based on anatomical constraints. We used this synchronized input as the driving input to an integrate-and-fire model of cortical responses and demonstrated that the tuning properties match closely to those measured in primary visual cortex. By modulating the overall level of synchronization at the preferred orientation, we show that efficiency of information transmission in the cortex is maximized for levels of synchronization which match those reported in thalamic recordings in response to naturalistic stimuli, a property which is relatively invariant to the orientation tuning width. These findings indicate evidence for a more prominent role of the feed-forward thalamic input in cortical feature selectivity based on thalamic synchronization.     

Reduced Slow-Wave Rebound during Daytime Recovery Sleep in Middle-Aged Subjects

Cortical synchronization during NREM sleep, characterized by electroencephalographic slow waves (SW <4Hz and >75 μV), is strongly related to the number of hours of wakefulness prior to sleep and to the quality of the waking experience. Whether a similar increase in wakefulness length leads to a comparable enhancement in NREM sleep cortical synchronization in young and older subjects is still a matter of debate in the literature. Here we evaluated the impact of 25-hours of wakefulness on SW during a daytime recovery sleep episode in 29 young (27y ±5), and 34 middle-aged (51y ±5) subjects. We also assessed whether age-related changes in NREM sleep cortical synchronization predicts the ability to maintain sleep during daytime recovery sleep. Compared to baseline sleep, sleep efficiency was lower during daytime recovery sleep in both age-groups but the effect was more prominent in the middle-aged than in the young subjects. In both age groups, SW density, amplitude, and slope increased whereas SW positive and negative phase duration decreased during daytime recovery sleep compared to baseline sleep, particularly in anterior brain areas. Importantly, compared to young subjects, middle-aged participants showed lower SW density rebound and SW positive phase duration enhancement after sleep deprivation during daytime recovery sleep. Furthermore, middle-aged subjects showed lower SW amplitude and slope enhancements after sleep deprivation than young subjects in frontal and prefrontal derivations only. None of the SW characteristics at baseline were associated with daytime recovery sleep efficiency. Our results support the notion that anterior brain areas elicit and may necessitate more intense recovery and that aging reduces enhancement of cortical synchronization after sleep loss, particularly in these areas. Age-related changes in the quality of wake experience may underlie age-related reduction in markers of cortical synchronization enhancement after sustained wakefulness.     

A Simple Rule for Dendritic Spine and Axonal Bouton Formation Can Account for Cortical Reorganization after Focal Retinal Lesions

Lasting alterations in sensory input trigger massive structural and functional adaptations in cortical networks. The principles governing these experience-dependent changes are, however, poorly understood. Here, we examine whether a simple rule based on the neurons'' need for homeostasis in electrical activity may serve as driving force for cortical reorganization. According to this rule, a neuron creates new spines and boutons when its level of electrical activity is below a homeostatic set-point and decreases the number of spines and boutons when its activity exceeds this set-point. In addition, neurons need a minimum level of activity to form spines and boutons. Spine and bouton formation depends solely on the neuron''s own activity level, and synapses are formed by merging spines and boutons independently of activity. Using a novel computational model, we show that this simple growth rule produces neuron and network changes as observed in the visual cortex after focal retinal lesions. In the model, as in the cortex, the turnover of dendritic spines was increased strongest in the center of the lesion projection zone, while axonal boutons displayed a marked overshoot followed by pruning. Moreover, the decrease in external input was compensated for by the formation of new horizontal connections, which caused a retinotopic remapping. Homeostatic regulation may provide a unifying framework for understanding cortical reorganization, including network repair in degenerative diseases or following focal stroke.     

Synaptic connections of physiologically identified geniculocortical axons in kitten cortical area 17.

Single geniculocortical axons were recorded in the cortical white matter of kittens and adult cats by using micropipettes filled with horseradish peroxidase (HRP). Of 41 axons recovered in 4-5 week old kittens, three well-filled axons arborized in area 17; the remainder were incomplete or arborized in area 18. One axon had Y-like physiological properties, two were X-like. They were recovered from two 34-day-old kittens. All three axons formed clustered arborizations, mainly in layer 4A. Electron microscopic (EM) analysis of 50 boutons from kitten and 38 boutons from adult controls revealed that the boutons from kitten made synapses more frequently on spines (91% of targets) than did the boutons from the adult (71%). One X-like axon in kitten also had a collateral projection that made synapses in layer 1; this has not been seen in adult cats. In overall extent, the axons from kitten fell within the adult range.     

Spiking behavior and epileptiform oscillations in a discrete model of cortical neural networks

Summary We investigate the phenomenon of epileptiform activity using a discrete model of cortical neural networks. Our model is reduced to the elementary features of neurons and assumes simplified dynamics of action potentials and postsynaptic potentials. The discrete model provides a comparably high simulation speed which allows the rendering of phase diagrams and simulations of large neural networks in reasonable time. Further the reduction to the basic features of neurons provides insight into the essentials of a possible mechanism of epilepsy. Our computer simulations suggest that the detailed dynamics of postsynaptic and action potentials are not indispensable for obtaining epileptiform behavior on the system level. The simulation results of autonomously evolving networks exhibit a regime in which the network dynamics spontaneously switch between fluctuating and oscillating behavior and produce isolated network spikes without external stimulation. Inhibitory neurons have been found to play an important part in the synchronization of neural firing: an increased number of synapses established by inhibitory neurons onto other neurons induces a transition to the spiking regime. A decreased frequency accompanying the hypersynchronous population activity has only occurred with slow inhibitory postsynaptic potentials.     

Disrupted neural synchronization in toddlers with autism

Autism is often described as a disorder of neural synchronization. However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms. Here, we show that disrupted synchronization is evident in the spontaneous cortical activity of naturally sleeping toddlers with autism, but not in toddlers with language delay or typical development. Toddlers with autism exhibited significantly weaker interhemispheric synchronization (i.e., weak "functional connectivity" across the two hemispheres) in putative language areas. The strength of synchronization was positively correlated with verbal ability and negatively correlated with autism severity, and it enabled identification of the majority of autistic toddlers (72%) with high accuracy (84%). Disrupted cortical synchronization, therefore, appears to be a notable characteristic of autism neurophysiology that is evident at very early stages of autism development.